Hitting the Sweet Spot

It's got full flavor at one-third the calories. It's safe for teeth and diabetics. And it's all-natural. The long, strange search for the ultimate sugar substitute.

Atkins. The Zone. Slim-Fast Dark Chocolate Fudge Shakes. For decades, hucksters and scientists alike have offered an endless string of fixes for our oversize appetites and waistlines. But while their wallets may be getting thicker, we aren't getting any thinner. An even more lucrative future awaits the inventor who can give the US what we really want: the ability to eat anything in sight and not get fat.

When it comes to replacing sugar, plenty have tried. The history of sugar substitutes is a catalog of strange scientific accidents stretching back more than a century. In 1879, chemists Ira Remsen and Constantine Fahlberg synthesized a derivative of coal tar called orthobenzoyl sulfimide. One day, Fahlberg spilled the substance on his hand, which later that evening he touched to his mouth. It tasted sweet. He filed for a patent and called the substance saccharin. In 1937, a University of Illinois grad student discovered another sweetener when he set his cigarette on a lab bench during an experiment - testing a would-be antifever drug - and then took a drag off the cyclamate-coated end. In 1965, a chemist named Jim Schlatter was working on a compound to treat gastric ulcers. He licked his finger to grab a sheet of paper and tasted aspartame for the first time. Then there was the 1976 discovery of sucralose by a King's College student working with chemically altered sugars. The student - not a native English speaker - mistook his professor's instruction to "test" the material and tasted a mouthful.

Unfortunately, these products of serendipity haven't lived up to their promise. Consider the health scares - cyclamates are banned in the US; saccharin can't shake its link to cancer. And there's the fact that most sweeteners have just plain left a bad taste in our mouths. Remember Tab? Diet sodas may be better today, but they're still not quite right. Artificially sweetened foods remain a pale reflection of the real thing.

Now comes a sweetener that does all the wannabes one better: It's natural. It actually is sugar. Unlike high-intensity artificial sweeteners, tagatose looks, tastes, and cooks like sugar. It's 92 percent as sweet as table sugar but with only 38 percent of the calories. Studies suggest it prevents weight gain and doesn't cause cavities. It's safe for diabetics and may even help combat the disease.

Sound too good to be true? Take a walk down to your local 7-Eleven and check it out for yourself. Tagatose has cleared the FDA hurdles; it hit the US market in Pepsi's Diet Slurpee in August. Now Pepsi is looking beyond frozen beverages, testing tagatose in combination with other sweeteners to improve the taste of its diet sodas. Other brands could follow. Kellogg's obtained a patent in 2002 to use tagatose in "improved sucrose-free, noncarcinogenic, reduced-calorie, insulin-independent" sweet cereals. Wrigley and Kraft have patents of their own. As a result, tagatose could begin popping up in products on US grocery store shelves by the end of the year. And its arrival will mark the culmination of the most bizarre sugar substitute discovery of all.

On a sunny morning in his office in Beltsville, Maryland, 79-year-old Gilbert Levin is hunched over a press release from the Danish dairy company Arla Foods. The firm, which holds an exclusive license to food uses of tagatose, has begun production at its first commercial facility, with a second plant on the drawing board. Levin's company, Spherix, will earn a 25 percent royalty on Arla net sales. And in Levin's mind, Slurpees are only the beginning. He wants tagatosein chocolate, cookies, and cakes - and in sugar bowls.

Levin's long, strange search for the ultimate sugar replacement started three decades ago, when he stumbled upon chiral chemistry, the well-established principle that complex molecules exist in "right-handed" and "left-handed" forms, known as enantiomers

There's an easy way to understand chirality. Hold out your hands, palms facing each other. Imagine that each hand is the chemical structure of a molecule. Most complex molecules are chiral. Like your hands, the two structures of chiral molecules - in sugars, they're referred to as D and L, from the Latin dexter and laevus - differ only in the arrangement of their elements. Put your hands together and they seem to match exactly. In the same way, the common sugar D-glucose is the mirror image of L-glucose, its rare counterpart. But put your hands down one on top of the other, both facing down, and you'll see that they're not identical at all; they're what chemists call non-superimposable.

Two enantiomers of a molecule will respond identically in a chemical reaction, but not so in biological systems. Proteins and cell receptors are designed to react only with particular enantiomers. For example, the enzymes in your stomach can digest only right-handed sugars. Just as a glove fits only on the proper hand, our bodies distinguish between the enantiomers of any given molecule.

Louis Pasteur discovered chirality in the 19th century. But the practical implications were few until the past 15 years, when the pharmaceutical industry began to exploit it. Previously, drugs were produced in a mixture of equal parts right-handed and left-handed enantiomers. The problem with such mixtures is that the correct enantiomer might cure a disease, but the wrong one could wreak havoc on the body. Such was the case with thalidomide in the 1960s. One version cured morning sickness during pregnancy; the other caused birth defects. By the late 1980s, researchers had improved methods of synthesizing single enantiomers, which led to a revolution in pharmaceuticals. Suddenly, drug companies could reduce dosages and avoid side effects. Today, chiral pharmaceuticals are a $147 billion business. Lipitor, Zoloft, and Paxil are all single-enantiomer drugs.

Neither chemist, biologist, nor businessman by training, Levin was introduced to chirality - and with it, the inspiration for tagatose - while taking a biochemistry class at Johns Hopkins University in the early '60s. For Levin, it was a third tour at Hopkins; he received a bachelor's in 1947 and a master's in sanitary engineering a year later. In the mid-'50s, while working for the Washington, DC, health department, he had an idea for a faster method of checking beaches and swimming pools for bacteria. He added radiation-laced nutrients to the water samples. If there were bacteria present, he figured, they'd eat the nutrients and give off radioactive CO2, detectable by a Geiger counter. The experiment worked, but it was never widely adopted. "Something about the word radioactive scared the bejesus out of people," he sighs.

It didn't scare NASA. Levin persuaded the agency to bring his test to Mars. On July 20, 1976, the Viking I lander touched down on the Red Planet to gather data about its atmosphere and surface - and to use Levin's invention to look for life. The lander would place Martian soil in a container with radiation-laced nutrients. If microbes were present, they - just like the swimming-pool bacteria - would eat the nutrients and release radioactive CO2. If radioactivity was detected, it could mean only one thing: life.

Michelle AsselinGilbert Levin made his discovery two decades ago; now a mass-market version of tagatose is finally within reach.The results came back positive, stunning NASA researchers. The Viking heated the sample to kill any microbes and tested again as a control. By the parameters of the experiment, Levin discovered life. The problem was that two other life-detection experiments came up negative, as did a test for organic matter - a precursor to all known life. The official NASA line: Levin's test had been fooled by oxidants in the soil.

Levin still believes he discovered life on Mars. Twenty-seven years after his initial experiment, attitudes about the possibility of Martian life have changed. That doesn't mean anyone's admitting Levin was right, but he has become harder to dismiss outright. "I agree that his experiment found something very interesting," says Chris McKay, a Mars expert at NASA's Ames Research Center, who sides with the non-life camp. "We need to go and find out what it is. But I disagree that we can conclude already that it is life."

While the Mars experiment may be considered inconclusive at best, it led Levin to tagatose. Persuaded by NASA that he needed to improve his credentials, Levin returned to Johns Hopkins for his PhD in environmental engineering. That's where he learned that the body handles each type of molecule differently. It gave him an idea: If he could find a left-handed sugar, human enzymes wouldn't be able to process it. But would the substitutes still be as sweet as right-handed table sugar? A search of the literature turned up one paper examining L-glucose. The conclusion: bitter. Levin ordered some anyway and set up a taste panel at his new company, Spherix (née Biospherics). To his surprise, no one could tell the difference between the L and D versions. In 1981, Levin patented 10 left-handed sugars for use in foods and began looking for ways to make them. "We found several that were quite good," he says, "but we could never manufacture them cheaply enough."

For five years, Levin cycled through obvious candidates - L-sucrose, L-fructose - and found each too expensive to be viable. Finally, he decided to try L-tagatose, a rare left-handed sugar. When the maker accidentally sent him D-tagatose, he tested it. It was nearly as sweet as sugar, with similar baking and browning properties. By coincidence, D-tagatose is structurally similar to L-fructose, making it enough like a left-handed sugar that the small intestine absorbs only 20 to 25 percent of it. Translation: low-calorie. As it turns out, the perfect sugar Levin was searching for wasn't left-handed at all. But it took a lesson in chiral chemistry to find it.

Most crucially, the Spherix team devised an inexpensive way to make tagatose. Tiny quantities occur naturally in dairy products, and the process to derive it starts with whey, a byproduct of cheese-making. Lactose is extracted by removing proteins and then dissolved to form glucose and galactose. The glucose is sold off, and an enzyme is added to the galactose to form tagatose in bulk, either as syrup or crystals. Spherix patented the process in the late '80s.

Finding a way out of the lab and into the high-volume, low-margin food business proved daunting. Levin hustled for the money to build his own full-scale plant or find a partner, but talks with companies like Procter & Gamble fell through. Levin remembers the frustration. "They all told me, 'Once you've got the product developed and for sale, come back to us. We're not going to help you develop it,'" he says.

The longer it took him to produce tagatose, the more skeptical prospective customers became. Manfred Kroger, a professor emeritus at Penn State and an expert on low-calorie sweeteners, recalls, "People kept asking for samples, and Spherix said, 'We've only made one pound so far.' I thought the product was dead."

He wasn't the only one. Levin floundered for two decades trying to bring his discovery to market. Meanwhile, Spherix had to support his tagatose habit by expanding into a call-center business developed by Levin's wife, Karen. The company sets up operators to handle inquiries for government agencies and corporations. A handful of other Levin inventions never panned out. Today, Levin is seeking more than financial gain; he's looking for redemption. At the end of a 60-year career of near-misses, he hopes to finally silence skeptics in the scientific and business communities. "After all these false starts, as each year has gone by, it's like crying wolf," he says. "They're not going to believe it until they see it."

Levin whips out a set of keys, unlocks his desk, and rummages through a drawer. He pulls out a bag of tagatose-coated bran flakes and a chocolate bar, both creations of his Danish licensee. The bran is a little stale but sweet enough, and the chocolate tastes just like the real deal. He hands me a baggie of pure tagatose. I hold it up to the light, dab a little on my finger, and try it. A dead ringer for table sugar.

In a crowded sweetener market, it has to be. In addition to standbys like saccharin and aspartame, there are a handful of entrenched substitutes on store shelves - acesulfame potassium, stevia, and sugar alcohols like mannitol and sorbitol - used in myriad combinations to feed our ever growing appetite for diet food. The most troublesome competitor for tagatose is sucralose, sold as Splenda by McNeil Nutritionals, a subsidiary of Johnson & Johnson.

Sucralose is derived from sucrose through a process that replaces three hydroxyl atoms with chlorine, creating a crystal 600 times sweeter than sugar. Unlike saccharin and aspartame (but like tagatose), sucralose is heat-resistant, so you can bake with it. But it behaves differently than sugar. Foods sweetened with sucralose won't brown as well and they cook more quickly, so recipes may need to be adjusted. Splenda hit the market in 1998 and has since made its way into hundreds of big-name products (see chart, opposite page).

Jason Mecier / WIRED

For Levin, the success of sucralose is a frustrating case of what might have been. He licensed tagatose to Arla in 1996, but it took five years for the Danes to obtain the FDA's "generally recognized as safe" status in the US - and then only as a food additive. It's taken another two years for Arla to build the first plant. (Arla obtained approval for tagatose in Australia, New Zealand, and South Korea this summer and expects Japan and Europe to follow.) And while Arla was seeking regulatory approval, sucralose came to market.

When tagatose finally hits the mainstream, it will offer distinct advantages over its competitors. It can be used as a one-to-one sugar replacement. It's safe for teeth, stimulates beneficial bacteria in the stomach, and has been shown to enhance flavor. And, as the only FDA-approved natural sugar substitute, tagatose avoids the anxiety about chemical derivatives. When studies in the 1970s showed that rats developed bladder tumors from consuming saccharin, the FDA proposed banning it, only to be overruled by Congress. Saccharin's stained image, though, has made it hard for other sweeteners to gain acceptance. The NutraSweet Web site's FAQ is devoted to answering charges that aspartame causes brain tumors, epileptic seizures, even weight gain.

Such public suspicion could give all-natural tagatose a huge marketing edge. The body might not distinguish between naturally and chemically derived food, but consumers do. Tagatose could hitch a ride on the same sentiments driving resistance to GM foods and the burgeoning infatuation with organics. The growing concern over obesity and diabetes could also fuel demand. A 1999 Spherix-funded study at the University of Maryland, published in Diabetes, Obesity, and Metabolism, showed that not only is tagatose safe for diabetics, it also blunts the rise in blood sugar from regular glucose consumption.

"It's going to go from a very minimal production rate to really starting to take over the market," says Paula Kalamaras, who coauthored a report on sweeteners for the Norwalk, Connecticut-based independent research firm Business Communications Company.

Levin isn't waiting around. In August, he traded in his CEO title to become Spherix's executive officer for science, leaving more time for his new gambit: commercializing tagatose, as Naturlose, for use in pharmaceuticals and toothpaste. Spherix is working with an unnamed university to manufacture samples that use sugar to sweeten a variety of medications. To convince the drug companies, Levin will unveil Spherix animal studies demonstrating any number of benefits that come with Naturlose: fertility enhancement (one study showed high pregnancy rates among tagatose-fed rats), biofilm prevention (tagatose breaks up films of bacteria that form on teeth and medical instruments), and even anemia treatment (tagatose enhances key blood factors critical to fighting the disease). In May, Spherix also patented a technology to utilize the chiral nature of perfumes. Levin's idea is to replace natural isomers of fragrance molecules - which lose their effectiveness when they are eaten by bacteria on the skin - with their mirror-image synthetic counterparts.

"My dad is one of these people who would very much like to be respected for his scientific achievements," says Levin's son Ron, an MIT radar systems engineer. "Many people have invested in him and tagatose, and many people have been waiting a long time for it to be developed, so he is very much motivated to bring the investors through to success."

But it may take more than motivation. Spherix and Arla are tied up in arbitration over the tagatose license contract. The patent on tagatose as an additive expires in 2006, the two patents on production methods a few years later. Levin hopes to see his sugar substitute flood the market before then. And two new NASA rovers slated to land on Mars in January could show that Levin was right all along. Talk about sweet vindication.